scholarly journals The effect of memantine, an antagonist of the NMDA glutamate receptor, in in vitro and in vivo infections by Trypanosoma cruzi

2019 ◽  
Author(s):  
Higo Fernando Santos Souza ◽  
Sandra Carla Rocha ◽  
Flávia Silva Damasceno ◽  
Ludmila Nakamura Rapado ◽  
Elisabeth Mieko Furusho Pral ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Side Effects ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Glutamate Receptor ◽  
Acute Phase ◽  
Chronic Phase ◽  
Parasitic Load ◽  
Inflammatory Infiltrates

AbstractChagas disease, caused by Trypanosoma cruzi, is a neglected tropical disease that affects 5-6 million people in endemic areas of the Americas. Presently, chemotherapy relies on two compounds that were proposed as trypanocidal drugs four decades ago: nifurtimox and benznidazole. Both drugs are able to eliminate parasitemia and to avoid seroconversion in infected people when used in the acute phase; however, their use in the chronic phase (the time when the majority of cases are diagnosed) is limited due to their serious side effects. Memantine is a glutamate receptor antagonist in the central nervous system of mammals that has been used for the treatment of Alzheimer’s disease. Our group previously reported memantine as a trypanocidal drug that is able to induce apoptosis-like death in T. cruzi. In the present work, we further investigated the effects of memantine on the infection of RAW 264.7 macrophages in vivo (in BALB/c mice). Here, we showed that memantine is able to diminish NO and Ca2+ entry in both LPS-activated and non-activated cells. These results, together with the fact that memantine was also able to reduce the infection of macrophages, led us to propose that this drug is able to activate a pro-oxidant non-NO-dependent cell defense mechanism. Finally, infected mice that were treated with memantine had diminished parasitemia, cardiac parasitic load, and inflammatory infiltrates. In addition, the treated mice had an increased survival rate. Taken together, these results indicate memantine to be a candidate drug for the treatment of Chagas disease.Author summaryChagas disease affects approximately 5 million people and is caused by the protist parasite Trypanosoma cruzi. Until now, there are no vaccines to prevent the human infection, and the therapy relies on the use of two drugs discovered more than 50 years ago, nifurtimox and benznidazole. Both drugs are efficient during the acute phase of the disease, however their efficacy in the chronic phase, when most of patients are diagnosed is controversial. In addition, both drugs are toxic, causing severe side effects during the treatment. For these reasons, new drugs against T. cruzi are urgently needed. In this work, we report a series of experiments supporting the repositioning of memantine, a drug used for treating Alzheimer’s disease, to treat the T. cruzi infection in an experimental infection model. Our data show that infected mice treated with memantine have diminished their parasitemia, cardiac parasitic load and inflammatory infiltrates and more importantly, they have diminished their mortality. Taken together, these results prompt memantine as a promising drug for treating Chagas disease.

Assessing the effectiveness of AS-48 in experimental mice models of Chagas’ disease

2020 ◽  
Vol 75 (6) ◽  
pp. 1537-1545 ◽  
Author(s):  
Rubén Martín-Escolano ◽  
Rubén Cebrián ◽  
Mercedes Maqueda ◽  
Desirée Romero ◽  
Maria José Rosales ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Enterococcus Faecalis ◽  
Chagas Disease ◽  
Chronic Infection ◽  
Acute Infection ◽  
Chronic Phase ◽  
Aetiological Agent ◽  
Promising Alternative ◽  
Parasitic Load

Abstract Objectives We report the in vivo trypanocidal activity of the bacteriocin AS-48 (lacking toxicity), which is produced by Enterococcus faecalis, against the flagellated protozoan Trypanosoma cruzi, the aetiological agent of Chagas’ disease. Methods We determined the in vivo activity of AS-48 against the T. cruzi Arequipa strain in BALB/c mice (in both acute and chronic phases of Chagas’ disease). We evaluated the parasitaemia, the reactivation of parasitaemia after immunosuppression and the nested parasites in the chronic phase by PCR in target tissues. Results AS-48 reduced the parasitaemia profile in acute infection and showed a noteworthy reduction in the parasitic load in chronic infection after immunosuppression according to the results obtained by PCR (double-checking to demonstrate cure). Conclusions AS-48 is a promising alternative that provides a step forward in the development of a new therapy against Chagas’ disease.

scholarly journals Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Solange L. de Castro ◽  
Denise G. J. Batista ◽  
Marcos M. Batista ◽  
Wanderson Batista ◽  
Anissa Daliry ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Chronic Phase ◽  
Public Health Problem ◽  
Term Therapy ◽  
High Morbidity ◽  
Synthetic Compounds ◽  
Natural And Synthetic

Chagas disease (CD), caused by Trypanosoma cruzi, affects approximately eight million individuals in Latin America and is emerging in nonendemic areas due to the globalisation of immigration and nonvectorial transmission routes. Although CD represents an important public health problem, resulting in high morbidity and considerable mortality rates, few investments have been allocated towards developing novel anti-T. cruzi agents. The available therapy for CD is based on two nitro derivatives (benznidazole (Bz) and nifurtimox (Nf)) developed more than four decades ago. Both are far from ideal due to substantial secondary side effects, limited efficacy against different parasite isolates, long-term therapy, and their well-known poor activity in the late chronic phase. These drawbacks justify the urgent need to identify better drugs to treat chagasic patients. Although several classes of natural and synthetic compounds have been reported to act in vitro and in vivo on T. cruzi, since the introduction of Bz and Nf, only a few drugs, such as allopurinol and a few sterol inhibitors, have moved to clinical trials. This reflects, at least in part, the absence of well-established universal protocols to screen and compare drug activity. In addition, a large number of in vitro studies have been conducted using only epimastigotes and trypomastigotes instead of evaluating compounds' activities against intracellular amastigotes, which are the reproductive forms in the vertebrate host and are thus an important determinant in the selection and identification of effective compounds for further in vivo analysis. In addition, due to pharmacokinetics and absorption, distribution, metabolism, and excretion characteristics, several compounds that were promising in vitro have not been as effective as Nf or Bz in animal models of T. cruzi infection. In the last two decades, our team has collaborated with different medicinal chemistry groups to develop preclinical studies for CD and investigate the in vitro and in vivo efficacy, toxicity, selectivity, and parasite targets of different classes of natural and synthetic compounds. Some of these results will be briefly presented, focusing primarily on diamidines and related compounds and naphthoquinone derivatives that showed the most promising efficacy against T. cruzi.

scholarly journals Effects of betamethasone on the course of experimentai. Infection with Trypanosoma cruzi

1986 ◽  
Vol 19 (3) ◽  
pp. 161-164 ◽  
Author(s):  
Frederico G.C. Abath ◽  
Yara M. Gomes ◽  
Eridan M. Coutinho ◽  
Silvia M.L. Montenegro ◽  
Maria E.B. Melo ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Acute Phase ◽  
Bacterial Infections ◽  
Acute Infection ◽  
Chronic Phase ◽  
Control Group ◽  
Cumulative Mortality ◽  
Histopathological Findings ◽  
Experimental Group

In this experiment, the effect of betamethasone administered in the early post- acute infection of mice by Trypanosoma cruzi was studied. This drug was administered during 30 days after the 42nd day of infection in a dose of 0.15 mg/day. The betamethasone treatment did not cause fresh outbreaks of parasitemia and the histopathological findings in the chronic phase were not different from those in the control group. The higher cumulative mortality after treatment in the experimental group was due to superimposed bacterial infections. Outbred albino mice infected with low numbers ofY strain Trypanosoma cruzi trypomastigotes were not suitable models for Chagas' disease, since after 7 months of observation only mild histological lesions developed in all the animais. Prolonged betamethasone treatment of mice infected with low numbers o/Trypanosoma cruzi of the Y strain, during the post-acute phase did not aggravate the course of infection.

scholarly journals Trypanosoma cruzi and experimental Chagas' disease: characterization of a stock isolated from a patient with associated digestive and cardiac form

1993 ◽  
Vol 26 (1) ◽  
pp. 25-33 ◽  
Author(s):  
E.C. Oliveira ◽  
M.M.A. Stefani ◽  
A.O. Luquetti ◽  
E.F. Vêncio ◽  
M.A.R. Moreira ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Digestive Tract ◽  
Chagas Disease ◽  
Acute Phase ◽  
Experimental Infection ◽  
Post Infection ◽  
Chronic Phase ◽  
Igg Antibodies ◽  
Histopathology Examination

A new Trypanosoma cruzi stock isolated from a patient in the chronic phase of Chagas' disease with the digestive and cardiac fortn of the disease was characterized by experimental infection in isogenic, susceptible, A/Sn strain mice. Parasitemia curves showed up to 1.7x10(6) parasites/ml and no mortality was observed up to 300 days post infection. Specific IgM was found in mice in the acute phase up to 40 days and also in the chronic phase. IgG antibodies yvere detected in the acute and chronic phase. Histopathology examination demonstrated myotropism to the digestive tract muscle layers and to the heart.

scholarly journals Trypanosoma cruzi infection associated with atypical clinical manifestation during the acute phase of the Chagas disease

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Lucia Rangel-Gamboa ◽  
Lirio López-García ◽  
Francisco Moreno-Sánchez ◽  
Irma Hoyo-Ulloa ◽  
María Elisa Vega-Mémije ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Acute Phase ◽  
Clinical Manifestations ◽  
Chronic Phase ◽  
Clinical History ◽  
Skin Lesions ◽  
Small Subunit ◽  
Serological Tests ◽  
Cutaneous Manifestations

Abstract Background Chagas disease (CD) is caused by the protozoan parasite Trypanosoma cruzi and is transmitted by triatomine insects. Clinical manifestations vary according to the phase of the disease. Cutaneous manifestations are usually observed in the acute phase (chagoma and Romaña’s sign) or after reactivation of the chronic phase by immunosuppression; however, a disseminated infection in the acute phase without immunosuppression has not been reported for CD. Here, we report an unusual case of disseminated cutaneous infection during the acute phase of CD in a Mexican woman. Methods Evaluation of the patient included a complete clinical history, a physical exam, and an exhaustive evaluation by laboratory tests, including ELISA, Western blot and PCR. Results Skin biopsies of a 50-year-old female revealed intracellular parasites affecting the lower extremities with lymphangitic spread in both legs. The PCR tests evaluated biopsy samples obtained from the lesions and blood samples, which showed a positive diagnosis for T. cruzi. Partial sequencing of the small subunit ribosomal DNA correlated with the genetic variant DTU II; however, serological tests were negative. Conclusions We present a case of CD with disseminated skin lesions that was detected by PCR and showed negative serological results. In Mexico, an endemic CD area, there are no records of this type of manifestation, which demonstrates the ability of the parasite to initiate and maintain infections in atypical tissues.

BloodstreamTrypanosoma cruziparasites from mice simultaneously express antigens that are markers of acute and chronic human Chagas disease

Parasitology ◽  
1991 ◽  
Vol 102 (3) ◽  
pp. 379-385 ◽  
Author(s):  
M. S. Leguizamon ◽  
O. E. Campetella ◽  
M. B. Reyes ◽  
C. F. Ibañez ◽  
M. A. Basombrio ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Acute Phase ◽  
Early Period ◽  
Chronic Phase ◽  
Blood Parasites ◽  
Expression Library ◽  
Antibody Specificities ◽  
Human Infections ◽  
Parasite Strains

Several recombinantTrypanosoma cruziproteins previously isolated were used as antigens to analyse antibody specificities present in sera from human infections. Some parasite proteins such as SAPA (Shed Acute Phase Antigen) are antigenic early after infection. Others, like antigens 1 and 30, are antigenic mainly during the chronic phase of the infection. To understand why different proteins are antigenic at different periods of infection, specificities of antibodies present in the sera of infected mice were compared with the antigens expressed by parasites collected directly from blood. Parasites collected during the acute parasitaemia peak expressed not only antigen SAPA, but also antigens 1 and 30. However, only antibodies against SAPA were frequently observed during the early period and also in the chronic phase of murine infection. Long-lasting antibodies against SAPA were detected regardless of the mouse and parasite strains used. Furthermore, all 8 recombinant clones detected in aT. cruziexpression library with pooled sera from acutely infected mice were homologous to the SAPA gene. These results show that even though parasites from the acute parasitaemia peak in mice may express simultaneously several proteins known to be antigenic, only antibodies against SAPA were consistently detected.

scholarly journals Interleukin-9 in Immunopathology of Trypanosoma cruzi Experimental Infection

2021 ◽  
Vol 11 ◽  
Author(s):  
Nadjania Saraiva de Lira Silva ◽  
Cristina Mary Orikaza ◽  
Fabiana Rodrigues de Santana ◽  
Luana Aguiar dos Santos ◽  
Bruno Ramos Salu ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Experimental Infection ◽  
Cardiac Fibrosis ◽  
Tissue Injury ◽  
Chronic Phase ◽  
Protective Role

Chagas’ disease is a parasitosis caused by Trypanosoma cruzi, which affects approximately 8 million people worldwide. The balance between pro- and anti-inflammatory cytokines produced during immunological responses contributes to disease prognosis and progression. Parasite tissue persistence can induce chronic inflammatory stimuli, which can cause long-term tissue injury and fibrosis. Chronic Chagas’ patients exhibit increased levels of interleukin (IL)-9, an important cytokine in the regulation of inflammatory and fibrogenic processes. Data on the role of IL-9 in other pathologies are sometimes contradictory, and few studies have explored this cytokine’s influence in Chagas’ disease pathology. Hence, the aim of this study was to evaluate the role of IL-9 in the progression of T. cruzi infection in vivo and in vitro. In vitro infection demonstrated that IL-9 reduced the number of infected cells and decreased the multiplication of intracellular amastigotes in both C2C12 myoblasts and bone marrow-derived macrophages. In myoblasts, the increased production of nitric oxide (NO) was essential for reduced parasite multiplication, whereas macrophage responses resulted in increased IL-6 and reduced TGF-β levels, indicating that parasite growth restriction mechanisms induced by IL-9 were cell-type specific. Experimental infection of BALB/c mice with T. cruzi trypomastigotes of the Y strain implicated a major role of IL-9 during the chronic phase, as increased Th9 and Tc9 cells were detected among splenocytes; higher levels of IL-9 in these cell populations and increased cardiac IL-9 levels were detected compared to those of uninfected mice. Moreover, rIL9 treatment decreased serum IL-12, IL-6, and IL-10 levels and cardiac TNF-α levels, possibly attempting to control the inflammatory response. IL-9 neutralization increased cardiac fibrosis, synthesis of collagens I and III, and mastocyte recruitment in BALB/c heart tissue during the chronic phase. In conclusion, our data showed that IL-9 reduced the invasion and multiplication of T. cruzi in vitro, in both myoblasts and macrophages, favoring disease control through cell-specific mechanisms. In vivo, IL-9 was elevated during experimental chronic infection in BALB/c mice, and this cytokine played a protective role in the immunopathological response during this phase by controlling cardiac fibrosis and proinflammatory cytokine production.

scholarly journals Resting and Dynamic Electrocardiography in Dogs with Experimental Chagas Cardiomyopathy

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
R. Oliveira Alves ◽  
A. A. Camacho ◽  
D. P. Junior
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Acute Phase ◽  
Sinus Tachycardia ◽  
Chronic Phase ◽  
Left Ventricular ◽  
Sinus Arrest ◽  
Chagas Cardiomyopathy ◽  
Electrocardiographic Monitoring ◽  
Electrocardiographic Changes

In the present protocol, adult dogs were infected with Trypanosoma cruzi, Bolivian strain, in order to show electrocardiographic changes by means of resting and dynamic (Holter) methods during acute and chronic phases of Chagas disease. In the acute phase there were sinus tachycardia, atrial and left ventricular overload, millivoltage suppression, electric alternance, and episodes of sinus arrest. At the parasitemia peak, atrium-ventricular block, junctional escape complexes, and atrium-ventricular dissociation were observed. Dogs that presented the most serious arrhythmias died suddenly. The increase in supraventricular and ventricular arrhythmic events, concentrated in the 4th postinoculation week, was visible at electrocardiographic monitoring. In the chronic phase, the events were restricted to first-degree atrium-ventricular blocks, premature ventricular complexes, ventricular bigeminy, and electrical alternation. It was concluded that the computerized and dynamic electrocardiography allowed to diagnose transient arrhythmia and to observe that the main tachyarrhythmic changes are concentrated at the acute phase concomitantly to the parasitemia peak.

scholarly journals Evaluation of Propranolol Effect on Experimental Acute and Chronic Toxoplasmosis using Q-PCR

2016 ◽  
pp. AAC.01323-16 ◽  
Author(s):  
Mahbobeh Montazeri ◽  
Mohammad Ali Ebrahimzadeh ◽  
Ehsan Ahmadpour ◽  
Mehdi Sharif ◽  
Shahabeddin Sarvi ◽  
...  
Keyword(s):  
Treatment Group ◽  
Side Effects ◽  
Acute Phase ◽  
Chronic Phase ◽  
Parasite Load ◽  
Post Treatment ◽  
Low Doses ◽  
Current Therapies ◽  
Pre Treatment

Current therapies against toxoplasmosis are limited and drugs have significant side effects and low efficacies. We evaluated the potential anti-Toxoplasmaactivity of propranolol 2, 3 mg/kg/dayin vivoin acute and chronic phases. Propranolol as the stabilizing cell membrane is a suitable drug for inhibiting the entrance ofToxoplasma gondii(T. gondii) tachyzoites into cells. The acute phase was performed using propranolol, pyrimethamine, propranolol plus pyrimethamine before (pre-treatment) and after (post-treatment) intraperitoneally challenge with 1×103tachyzoites of the virulent RH strain ofT. gondiiin Balb/c mice. Also in the chronic phase, treatment was performed 12 hours before intraperitoneally challenge with 1×106tachyzoites of the virulent RH strain ofT. gondiiin rats. One week (in acute phase) and two months (in chronic phase) after post infection, tissues were isolated and DNA was extracted. Subsequently parasite load was calculated using Q-PCR. In acute phase, in both groups, significant anti-Toxoplasmaactivity was observed using propranolol (P< 0.001). Propranolol in pre-treatment group showed higher anti-Toxoplasmaactivity than propranolol in post-treatment in brain tissues displaying therapeutic efficiency on toxoplasmosis. Also, propranolol combined with pyrimethamine reduced the parasite load as well as significantly increased survival of mice in pre-treatment group. In the chronic phase, anti-Toxoplasmaactivity was observed with propranolol and decreased parasite load in tissues. In conclusion, the presented results demonstrate that propranolol, as an orally available drug, is effective against acute and latent murine toxoplasmosis at low doses and increase efficiency of drug in combination therapy with propranolol-pyrimethamine.

scholarly journals The Colombian Strain of Trypanosoma cruzi Induces a Proinflammatory Profile, Neuronal Death, and Collagen Deposition in the Intestine of C57BL/6 Mice Both during the Acute and Early Chronic Phase

2022 ◽  
Vol 2022 ◽  
pp. 1-9
Author(s):  
José Rodrigues do Carmo Neto ◽  
Arthur Wilson Florêncio da Costa ◽  
Yarlla Loyane Lira Braga ◽  
Fernanda Hélia Lucio ◽  
Ana Luisa Monteiro dos Santos Martins ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Acute Phase ◽  
Neuronal Loss ◽  
Chronic Phase ◽  
Distal Portion ◽  
Experimental Models ◽  
Histopathological Analysis ◽  
Histopathological Changes ◽  
Necrosis Factor Alpha ◽  
Inflammatory Infiltrates

The objective of this study was to evaluate the histopathological changes caused by infection with the Colombian strain of Trypanosoma cruzi (T. cruzi) in the acute and chronic experimental phases. C57Bl/6 mice were infected with 1000 trypomastigote forms of the Colombian strain of T. cruzi. After 30 days (acute phase) and 90 days (early chronic phase) of infection, the animals were euthanized, and the colon was collected and divided into two parts: proximal and distal. The distal portion was used for histopathological analysis, whereas the proximal portion was used for quantification of pro- and anti-inflammatory cytokines. In addition, the weight of the animals and parasitemia were assessed. The infection induced gradual weight loss in the animals. In addition, the infection induced an increase in interferon gamma (IFNγ) and tumor necrosis factor-alpha (TNF-α) in the intestine in the acute phase, in which this increase continued until the early chronic phase. The same was observed in relation to the presence of intestinal inflammatory infiltrates. In relation to interleukin (IL)-10, there was an increase only in the early chronic phase. The Colombian strain infection was also able to induce neuronal loss in the myenteric plexus and deposition of the collagen fibers during the acute phase. The Colombian strain of T. cruzi is capable of causing histopathological changes in the intestine of infected mice, especially in inducing neuronal destructions. Thus, this strain can also be used to study the intestinal form of Chagas disease in experimental models.

Sign in / Sign up

Export Citation Format

Share Document